Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression

The systemic metabolic shifts that occur during aging and the local metabolic alterations of a tumor, its stroma and their communication cooperate to establish a unique tumor microenvironment (TME) fostering cancer progression. Here, we show that methylmalonic acid (MMA), an aging-increased oncometabolite also produced by aggressive cancer cells, activates fibroblasts in the TME, which reciprocally secrete IL-6 loaded extracellular vesicles (EVs) that drive cancer progression, drug resistance and metastasis. The cancer-associated fibroblast (CAF)-released EV cargo is modified as a result of reactive oxygen species (ROS) generation and activation of the canonical and noncanonical TGF beta signaling pathways. EV-associated IL-6 functions as a stroma-tumor messenger, activating the JAK/STAT3 and TGF beta signaling pathways in tumor cells and promoting pro-aggressive behaviors. Our findings define the role of MMA in CAF activation to drive metastatic reprogramming, unveiling potential therapeutic avenues to target MMA at the nexus of aging, the tumor microenvironment and metastasis. Methylmalonic acid (MMA) is increased in aging as well as produced by advanced tumors, and can drive pro-aggressive changes in these tumor cells. Here, the authors show that MMA can also act on fibroblasts in the tumor microenvironment, recruiting and activating them to further support tumor progression.

Automated summary

Systemic metabolic shifts during aging and local metabolic alterations of a tumor cooperate to establish a unique tumor microenvironment (TME). Methylmalonic acid (MMA) activates fibroblasts in the TME, which release IL-6 loaded extracellular vesicles (EVs) that drive cancer progression.